Biology subjects

Dechering, K. J.

Publications and source records attributed to Dechering, K. J..

6 recordsLinked to original sources

bioRxiv2024

An Accessible 3D HepG2/C3A Liver Spheroid Model Supporting the Complete Intrahepatocytic Lifecycle of Plasmodium falciparum

Current liver-stage Plasmodium falciparum models are complex, expensive, and largely inaccessible, hindering research progress. Here, we show that a 3D liver spheroid model grown from immortalized HepG2/C3A cells supports the complete intrahepatocytic lifecycle of P. falciparum. Our results demonstrate sporozoite infection, development of exoerythrocytic forms, and breakthrough infection into erythrocytes. The 3D-grown spheroid hepatocytes are structurally and functionally polarised, displaying enhanced albumin and urea production and increased expression of key metabolic enzymes, mimicking in vivo conditions - relative to 2D cultures. This accessible, reproducible model lowers barriers to malaria research, promoting advancements in fundamental biology and translational research.

microbiology↗

bioRxiv2022

A deep learning and digital archaeology approach for mosquito repellent discovery

Insect-borne diseases kill >0.5 million people annually. Currently available repellents for personal or household protection are limited in their efficacy, applicability, and safety profile. Here, we describe a machine-learning-driven high-throughput method for the discovery of novel repellent molecules. To achieve this, we digitized a large, historic dataset containing [~]19,000 mosquito repellency measurements. We then trained a graph neural network (GNN) to map molecular structure and repellency. We applied this model to select 317 candidate molecules to test in parallelizable behavioral assays, quantifying repellency in multiple pest species and in follow-up trials with human volunteers. The GNN approach outperformed a chemoinformatic model and produced a hit rate that increased with training data size, suggesting that both model innovation and novel data collection were integral to predictive accuracy. We identified >10 molecules with repellency similar to or greater than the most widely used repellents. We analyzed the neural responses from the mosquito antennal (olfactory) lobe to selected repellents and found a limited correlation between these responses and our GNN representation. This approach enables computational screening of billions of possible molecules to identify empirically tractable numbers of candidate repellents, leading to accelerated progress towards solving a global health challenge.

bioengineering↗

bioRxiv2022

Replenishing the malaria drug discovery pipeline: Screening and hit evaluation of the MMV Hit Generation Library 1 (HGL1) against asexual blood stage Plasmodium falciparum, using a nano luciferase reporter read-out

A central challenge of antimalarial therapy is the emergence of resistance to the components of artemisinin-based combination therapies (ACTs) and the urgent need for new drugs acting through novel mechanism of action. Over the last decade, compounds identified in phenotypic high throughput screens (HTS) have provided the starting point for six candidate drugs currently in the Medicines for Malaria Venture (MMV) clinical development portfolio. However, the published screening data which provided much of the new chemical matter for malaria drug discovery projects have been extensively mined. Here we present a new screening and selection cascade for generation of hit compounds active against the blood stage of Plasmodium falciparum. In addition, we validate our approach by testing a library of 141,786 compounds not reported earlier as being tested against malaria. The Hit Generation Library 1 (HGL1) was designed to maximise the chemical diversity and novelty of compounds with physicochemical properties associated with potential for further development. A robust HTS cascade containing orthogonal efficacy and cytotoxicity assays, including a newly developed and validated nanoluciferase-based assay was used to profile the compounds. 75 compounds (Screening Active hit rate of 0.05%) were identified meeting our stringent selection criteria of potency in drug sensitive (NF54) and drug resistant (Dd2) parasite strains (IC50 [≤] 2 {micro}M), rapid speed of action and cell viability in HepG2 cells (IC50 [≥] 10 {micro}M). Following further profiling, 33 compounds were identified that meet the MMV Confirmed Active profile and are high quality starting points for new antimalarial drug discovery projects.

microbiology↗

bioRxiv2021

The use of barcoded Asaia bacteria in mosquito in vivo screens for identification of systemic insecticides and inhibitors of malaria transmission

This work addresses the need for new chemical matter in product development for control of pest insects and vector-borne diseases. We present a barcoding strategy that enables phenotypic screens of blood-feeding insects against small molecules in microtiter plate-based arrays and apply this to discovery of novel systemic insecticides and compounds that block malaria parasite development in the mosquito vector. Encoding of the bloodmeals was achieved through recombinant DNA-tagged Asaia bacteria that successfully colonized Aedes and Anopheles mosquitoes. An arrayed screen of a collection of pesticides showed that chemical classes of avermectins, phenylpyrazoles and neonicotinoids were enriched for compounds with systemic adulticide activity against Anopheles. Using a luminescent Plasmodium falciparum reporter strain, barcoded screens identified 48 drug-like transmission blocking compounds from a 400-compound antimicrobial library. The approach significantly increases the throughput in phenotypic screening campaigns using adult insects, and identifies novel candidate small molecules for disease control.

bioengineering↗

bioRxiv2021

Preclinical characterization and target validation of the antimalarial pantothenamide MMV693183

Drug resistance and a dire lack of transmission-blocking antimalarials hamper malaria elimination. Here, we present the pantothenamide MMV693183 as a first-in-class acetyl-CoA synthetase (ACS) inhibitor to enter preclinical development. Our studies demonstrated attractive drug-like properties and in vivo efficacy in a humanized mouse model of Plasmodium falciparum infection. The compound showed exceptional in vitro activity against P. falciparum and P. vivax clinical isolates, and potently blocked P. falciparum transmission to Anopheles mosquitoes. Genetic and biochemical studies identified ACS as the target of the MMV693183-derived antimetabolite, CoA-MMV693183. MMV693183 was well adsorbed after oral administration in mice, rats and dogs. Pharmacokinetic - pharmacodynamic modelling predicted that a single 30 mg oral dose is sufficient to cure a malaria infection in humans. In conclusion, the ACS-targeting compound MMV693183 represents a promising addition to the portfolio of antimalarials in (pre)clinical development with a novel mode of action for the treatment of malaria and blocking transmission.

microbiology↗

bioRxiv2018

Antimalarial pantothenamide metabolites target acetyl-CoA synthesis in Plasmodium falciparum

Malaria eradication is critically dependent on novel drugs that target resistant Plasmodium parasites and block transmission of the disease. Here we report the discovery of potent pantothenamide bioisosteres that are active against blood-stage P. falciparum and also block onward mosquito transmission. These compounds are resistant to degradation by serum pantetheinases, show favorable pharmacokinetic properties and clear parasites in a humanized rodent infection model. Metabolomics revealed that CoA biosynthetic enzymes convert pantothenamides into drug-conjugates that interfere with parasite acetyl-CoA anabolism. In vitro generated resistant parasites showed mutations in acetyl-CoA synthetase and acyl-CoA synthetase 11, confirming the key roles of these enzymes in the sensitivity to pantothenamides. These new pantothenamides provide a promising class of antimalarial drugs with a unique mode of action.\n\nOne sentence summaryPantothenamides form antimetabolites that interfere with acetyl-CoA metabolism in the human malaria parasite Plasmodium falciparum

pharmacology and toxicology↗